DESCRIPTION(Adapted from Investigator's Abstract): The cells of an organism are continually exposed to adverse environmental conditions including extreme temperatures, osmotic pressure, toxic chemicals, and UV radiation. Viral, bacterial, and parasitic infections can also induce cellular stress. Currently, the mammalian stress-signaling pathway is poorly understood. It consists of several protein networks that extend from the plasma membrane to the cell nucleus. There are receptors that "sense" adverse conditions then activate cascades of signaling molecules to initiate the cellular stress response. This response usually protects the cells and assists in their recovery, but can also cause apoptosis in order to remove damaged or transformed cells. Very few components of the stress-signaling pathway have been characterized thus far. Known components are members of very diverse families or proteins, including membrane receptors, kinases, proteases, and transcription factors. The applicants studies on stress-signaling are focused on the function of a stress-activated kinase, Mxi2. Mxi2 is an alternative spliced form of p38 stress-activated kinase, isolated as a Max-interacting protein and expressed exclusively in the kidney. p38 is activated in response to a number of stress signals including osmotic shock, UV irradiation, polysaccharides, and several cytokines (TGF-a, IL-1), and others). P38 is also the target of a number of anti- inflammatory drugs and has a role both in ischemia and septic shock. It is the aim of the proposal to use both genetic and biochemical approaches to study the regulation of Mxi2 by stress and its function in cell recovery or apoptosis, especially in kidney after ischemia. These studies will help define the role of Mxi2 in stress-signaling, distinct from that of p38. They will also characterize the molecular events that follow kidney ischemia and provide insight into the determinants of recovery from acute renal failure.